River Ganges Inspires MRSA Treatment

In the winter of 1895, a British scientist made a discovery in the River Ganges that is now informing cutting edge research in Bangalore on how to combat antibiotic resistant disease.

M.E. Hankin found that the waters of India’s most sacred river, as well as those flowing in the Yamuna, contained antiseptic properties that killed the cholera germ. This was identified 22 years later, in 1917, as the work of a bacteriophage.

Phage therapy was used to treat a range of bacterial diseases but fell out of favor after the 1928 discovery and development of penicillin and other antibiotics. Only hospitals in some parts of Eastern Europe including Georgia continued to use the phage treatment.

But with the seemingly unstoppable march of antibiotic resistant bacteria, the bacteriophage is, according to scientists working on its development, undergoing a renaissance. It is now informing the design of a new treatment for the infection-causing bacterium MRSA (Methicillin-Resistant Staphylococcus Aureus.)

The technology could provide hope in the treatment of gram-negative bacteria carrying the enzyme NDM-1 (New Delhi Metallo-beta-lactamase-1), which confers resistance against carbopenems, the antibiotics of last resort.

In a laboratory in Bangalore, scientists from biotechnology company GangaGen Inc. are developing the treatment based on the enzyme that phages use to destroy bacterial cell walls.

Bharathi Sriram, vice-president of research and development at GangaGen, said the enzyme breaks down the cell wall in minutes so there is very little time for the bacterium to build up resistance. Antibiotics however can take days to have an effect, allowing the bacteria to develop defenses.

“Phages are like moon-landers,” Ms. Sriram told The Wall Street Journal’s India Real Time. “They can work on a cell wall; find the right receptors and latch on to them by lowering their base plate.”

Highly specific enzymes on the phage’s base plate then break down the bacterial cell wall before injecting their DNA and replicating to cause bactericide, Ms. Sriram said.

GangaGen scientists have identified and isolated the enzyme able to break down the cell wall of Stapylococcus Aureus, commonly known as MRSA, the bacterium that causes difficult-to-treat-infections often contracted by patients in hospital for surgery.

The major route of entry of the MRSA bacterium is from the patients’ own bodies because they can harbor it innocuously in their nostrils or on their skin, said Janakiraman Ramachandran, GangaGen’s founder and chairman.

“But when it gets in the bloodstream it secretes toxic materials,” said Mr. Ramachandran, who was head of Research and Development at AstraZeneca in Bangalore in the 1980s.

“We are targeting the clearance of the bacterium from the nasal carriage [of patients who are going to undergo surgery],” he said, adding that this makes it easier to prevent the entry of MRSA into the bloodstream.

GangaGen has completed preclinical toxicological studies using the enzyme and is carrying out phase one and two clinical trials for safety and efficiency on patients in Singapore.

“We tried initially to do the trials in India but the delays were horrendous; we could not predict when we would be able to get permission,” said Mr. Ramachandran, who runs GangaGen from a California-based holding company.

He says he chose to base his laboratory in Bangalore because of the “abundant talent” there and lower operating costs. Initially he funded GangaGen’s research himself, but now has help from angel investors in the U.S.

The company has patented the technology and phase one trials should be completed in the fall. The next stage is to partner with a big pharmaceutical company to conduct the more expensive phase three clinical trials.

A drawback of phage therapy compared to antibiotic treatment is that the enzymes are highly specific and only act on particular bacteria. “The difficulty is we have to properly diagnose the infection and use the appropriate phage,” Mr. Ramachandran said.

Abdul Ghafur, a Chennai-based consultant in infectious diseases who is among those leading the efforts in India to raise awareness of antibiotic resistance, says phage therapy, though not yet in use in India, has potential.

“Phage therapy is still in experimental stage but it’s worth exploring,” he said.

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